This application addresses the broad Challenge Area, (11) Regenerative Medicine, and specific Challenge Topic, "11-HL-101, Develop cell-based therapies for cardiovascular, lung, and blood diseases." Cell-based therapies have spawned the emerging discipline of regenerative medicine and offer new paradigms for advancing patient care. Despite this potential, to date the outcomes of cell- based therapies to treat myocardial infarction are controversial with some positive, some negative, and even some detrimental results. We opine that treatment of acute myocardial infarction with stem cells may not be the most effective regenerative therapy rather stimulation of coronary collateral growth is the most likely strategy to produce an immediate benefit in the treatment of ischemic heart disease. The growth of coronary collaterals could prevent sudden death and myocardial infarction. Moreover, stimulation of collateral growth is a simpler goal than rebuilding myocardium in an infarct zone, where a complete arterial, capillary, and venous vasculature must be rebuilt along with myocytes and a conductible system working as a functional and electrical synctium. Notwithstanding this issue, in some regards the clinical studies may be premature insofar as several details, e.g., the most promising target patient population, the best cell type and number of cells to use, the optimal methods and timing of delivery have not yet been optimized. Within the context of this Challenge Area, in this application we propose to expand on practical aspects of stem cell therapies by determining which type of stem cell best promotes coronary collateral growth in the heart, the conditions in the heart that are conducive to promote collateral growth, and finally, a method to render stem cells resistant to oxidative stress to promote their survival and enhance their biological effect in models of vascular disease with existing oxidative stress. Specifically we propose 3 aims: 1) To determine which type of adult stem cell best stimulates coronary collateral growth. 2) To determine the conditions of the heart that are conducive for stem cell stimulation of collateral growth. 3) To determine if stem cells selected for resistance to oxidative stress will better stimulate coronary collateral growth in vascular disease than non-selected cells. These aims are built upon an interdisciplinary team with experience ranging from virology, study of embryonic stem cells, molecular biology, biochemistry, physiology, and vascular biology. PUBLIC HEALTH RELEVANCE: The outcomes of cell-based therapies to treat myocardial infarction are controversial with some positive, some negative, and even some detrimental results. However, we opine that treatment of acute myocardial infarction with stem cells may not be the most effective use for regenerative therapies, rather stimulation of coronary collateral growth is likely the most likely strategy to produce an immediate benefit in the treatment of ischemic heart disease using regenerative therapies. Our goals are to determine which adult stem cell, and under what specific conditions, best stimulates coronary collateral growth in the heart.